PROJECT 3 - SUMMARY/ABSTRACT Hepatocellular injury, hepatic fibrosis, and cirrhosis leading to liver failure have been described in a subset of patients with urea cycle disorders (UCD). In addition, there are reports of abnormal liver function during acute episodes of hyperammonemia in several disorders, including ornithine transcarbamylase deficiency (OTCD), and there are single case reports of hepatocellular carcinoma in UCD. Common histopathologic findings in the liver of individuals with UCD include hepatocyte enlargement, increased glycogen deposition, and steatosis. However, there are no recommendations for long-term surveillance for chronic hepatic complications. Although serum aminotransferases and markers of synthetic function are used to monitor hepatic disease, the sensitivity of such assays to detect progression of liver disease is low. Recently, several non-invasive biomarkers for liver fibrosis including serum biomarker panels and various forms of elastography have been validated for predicting the degree of fibrosis in patients with a variety of chronic liver diseases. In this project, we propose to use these non-invasive tools to assess the extent and prevalence of liver disease in a large cohort of individuals with UCD. Data from the Longitudinal Study of UCD, Urea Cycle Disorders Consortium (UCDC) Project 1, show that the risk for chronic hepatocellular injury is higher in distal UCD (e.g., argininosuccinate lyase deficiency ? ASLD, citrullinemia ? ASS1D, and arginase deficiency - ARG1D) compared to OTCD, a proximal UCD. We hypothesize that liver fibrosis, as measured by non-invasive biomarkers, is also a significant and underestimated complication of distal UCD and that both steatosis and glycogen accumulation contribute to the etiology of the liver disease. To test this hypothesis, we will compare serum biomarkers for fibrosis in individuals with ASS1D, ASLD, and ARG1D vs. OTCD, and we will test whether elevation in serum biomarkers for fibrosis correlate with liver stiffness as measured by magnetic resonance elastography (MRE). Lastly, we will histopathologically score fibrosis stage and steatosis grade, and quantify the glycogen content in hepatic explants and biopsies from two UCDC liver transplant centers in order to determine the prevalence of these complications in UCD. Overall, this will be the largest, comprehensive study of liver disease in UCD. This study will inform our understanding of the natural history of liver disease in UCD, provide the basis for the development of new biomarkers for assessing liver disease in UCD, and validate endpoints that could be used in the future to assess efficacy of interventions for the prevention and/or therapy of liver disease in UCD.